Abstract 2149: Association of tumor fusion burden with immune presence and androgen sensitivity in prostate cancer
Authors: Marie Wagle, Kobe Yuen, Edward E. Kadel, Thomas Holcomb, Shrividhya Srinivasan, Joseph Castillo, Dan Halligan, Adrian Carr, Max Bylesjo, Julian Augley, Simone Daminelli, Mark Kockx, Yannick Waumans, Jennifer Giltnane, Zineb Mounir
Journal: Cancer Research (2019)

Abstract Introduction: Prostate cancer (PrCa) is the second leading cause of cancer death in men. Despite having a lower tumor mutation burden (TMB) than most tumor types (1), multiple gene fusions such as TMPRSS2-ERG have been characterized in prostate cancer and have been linked to aggressive disease (1). Individual tumor samples may contain multiple fusions and it is unknown whether these fusions could increase tumor immunogenicity. Here we investigated the effects of fusion burden on the expression of key molecular and immune effectors in prostate cancer specimens representing different stages of disease progression and androgen sensitivity (hormone sensitive vs metastatic castrate resistant prostate cancer (mCRPC)). Methods: 187 prostate samples taken from different stages of PrCa including Early/intermediate (n:30), late (n:112) and metastatic disease (n:9) were interrogated by RNASeq and assessed for mutation burden (mutations/MB of the genome) and fusion burden (number of fusions/10,000 genes profiled in each sample). To characterize the immune microenvironment, stromal TILS, % immune infiltrate, CD8+ T-cells, and PDL-1 expression were assessed by immunohistochemistry (IHC). Key molecular and immune gene signatures derived from the expression data were clustered according to disease stage, mutation or fusion burden, and hormone sensitive vs mCRPC disease (determined by mCRPC score from (2)). Results and Conclusion: TMB was very low across all samples analyzed (0.01-1.2 mutations per MB) while fusion burden ranged from 0 to 34 fusions/10,000 genes (up to 70 fusion(s) per sample) and was inversely correlated to TMB and not associated with disease stage. High fusion burden across samples correlated with high cell cycle progression and AR signaling (P&amp;lt;0.0001), ERG and ETS transcriptional activity (P&amp;lt;0.005) along with a modest increase in stromal TILs, % immune infiltrate and PDL-1 expression on immune cells. Fusion burden also correlated with immune signatures representing activation of M1 macrophages, checkpoint inhibitors, and T-cell activity (IFNγ-induced and T-effector signatures) (P&amp;lt;0.0001) whilst inversely correlating with an immune suppressor signature (P&amp;lt;0.01). High fusion burden also correlated with a high mCRPC score (P&amp;lt;0.0001), representing the most aggressive disease. Samples with a high mCRPC score also had gene signature scores suggesting high AR signaling, PI3K signaling, cell cycle progression and class I antigen presentation, and low expression of neuroendocrine tumor markers, NK cell and immune suppressor signatures. Our data suggest that high fusion burden may be associated more closely with immunogenicity and disease prognosis than TMB in PrCa and that tumors with high fusion burden could be potential candidates for immunotherapy. References(1) Chalmers et al. (2017), Genome Medicine Apr 19: 9(1):34 9:34.(2) Sharma N.L et al. (2013), Cancer Cell: Jan 14: 23(1):35-47. Note: This abstract was not presented at the meeting. Citation Format: Marie Wagle, Kobe Yuen, Edward E. Kadel, Thomas Holcomb, Shrividhya Srinivasan, Joseph Castillo, Dan Halligan, Adrian Carr, Max Bylesjo, Julian Augley, Simone Daminelli, Mark Kockx, Yannick Waumans, Jennifer Giltnane, Zineb Mounir. Association of tumor fusion burden with immune presence and androgen sensitivity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2149.